Minerals and blood pressure

The mineral elements sodium, potassium, calcium and magnesium play a central role in the normal regulation of blood pressure. In particular, these mineral elements have important interrelationships in the control of arterial resistance. These elements, especially sodium and potassium, also regulate the fluid balance of the body and, hence, influence the cardiac output. Evidence shows that the present levels of intake of mineral elements are not optimum for maintaining normal blood pressure but predispose to the development of arterial hypertension. Research results suggest that without sodium chloride (common salt) and other sodium compounds being added to the diet arterial hypertension would be virtually non existent. Moreover, blood pressure would not rise with age. In communities with a high consumption of added sodium, a high intake of potassium and, possibly, magnesium seem to protect against the development of arterial hypertension and the rise of blood pressure with age. A marked reduction of sodium intake is effective in treating even severe hypertension. A moderate restriction of sodium intake or an increase in potassium intake exert remarkable antihypertensive effects, at least in some hypertensive patients. Magnesium and possibly also calcium supplements may be effective in reducing blood pressure in some hypertensives. In hypertensive patients treated with drugs sodium restriction and potassium and magnesium supplementation enhance the therapeutic effect, reduce the number and dosage, and lessen the adverse effects of prescribed antihypertensive drugs. Hence, a fall in sodium consumption and increases in potassium and magnesium consumption are useful in preventing and treating arterial hypertension.     

Minerals and Blood Pressure

The mineral elements sodium, potassium, calcium and magnesium play a central role in the normal regulation of blood pressure. In particular, these mineral elements have important interrelationships in the control of arterial resistance.

These elements, especially sodium and potassium, also regulate the fluid balance of the body and, hence, influence the cardiac output. Evidence shows that the present levels of intake of mineral elements are not optimum for maintaining normal blood pressure but predispose to the development of arterial hypertension.

Research results suggest that without sodium chloride (common salt) and other sodium compounds being added to the diet arterial hypertension would be virtually non existent. Moreover, blood pressure would not rise with age. In communities with a high consumption of added sodium, a high intake of potassium and, possibly, magnesium seem to protect against the development of arterial hypertension and the rise of blood pressure with age.

A marked reduction of sodium intake is effective in treating even severe hypertension. A moderate restriction of sodium intake or an increase in potassium intake exert remarkable antihypertensive effects, at least in some hypertensive patients. Magnesium and possibly also calcium supplements may be effective in reducing blood pressure in some hypertensives.

In hypertensive patients treated with drugs sodium restriction and potassium and magnesium supplementation enhance the therapeutic effect, reduce the number and dosage, and lessen the adverse effects of prescribed antihypertensive drugs. Hence, a fall in sodium consumption and increases in potassium and magnesium consumption are useful in preventing and treating arterial hypertension.     

Calcium and hypertension

A possible relationship between dietary calcium intake and blood pressure has been the focus of considerable recent observational and experimental research. To provide a current perspective, we have reviewed and summarized the epidemiologic data, evidence suggesting abnormalities in calcium metabolism in human hypertension, studies evaluating calcium supplementation in various hypertension populations, and data that may help elucidate possible blood pressure-lowering mechanisms of calcium supplementation. An important relationship between "calcium metabolism" and "salt-sensitivity" is emerging and appears to be providing insights into potential mechanisms that account for the antihypertensive properties of dietary calcium in certain individuals. More experimental work needs to be performed to further define the individuals with hypertension who demonstrate a blood pressure-lowering response to dietary calcium supplementation.     

Cytosolic free calcium and intracellular calcium stores in neutrophils from hypertensive subjects

Alterations in intracellular calcium have been implicated in the pathogenesis of essential hypertension. To see whether this is a generalized phenomenon we assessed cytosolic free calcium and intracellular calcium stores in neutrophils from normo- and hypertensive subjects, by trapping the fluorescent calcium indicator quin2 in intact cells. Ten patients with untreated essential hypertension were compared with 10 age- and sex-matched normotensive subjects. The levels of cytosolic free calcium and intracellular calcium stores releasable by the calcium ionophore ionomycin did not differ. No significant relationship was found between blood pressure and the calcium parameters in all 20 subjects studied. The results indicate that essential hypertension is not associated with a membrane defect in calcium handling of all human cell systems, leading to generalized increases in resting values of cytosolic free calcium. Neutrophils do not appear to be a good model for intracellular calcium handling in vascular smooth muscle.     

Salt and hypertension: recent advances and perspectives

Dietary sodium intake has long been considered important in the genesis and maintenance of hypertension. This view is predicated on the results of epidemiologic observations, experiments in animals, investigations at the cellular level, and the results from dietary intervention trials. In the past decade a considerable body of new evidence has been gathered. A comprehensive, world-wide epidemiologic investigation involving over 10,000 subjects found significant relationships between sodium excretion and blood pressure levels and between sodium excretion and the slope of increase in blood pressure with age. The relationships, however, are not as straight-forward as previously proposed. Investigations in animals and in human subjects emphasize the genetic nature of salt sensitivity of blood pressure. A putative genetic marker has been suggested in human studies. At the cellular level, increases in sodium-lithium countertransport, sodium-hydrogen exchange, and cytosolic calcium level have been identified. Cytosolic calcium level was found to increase in lymphocytes in response to a high-salt diet in salt-sensitive individuals with hypertension, yet the identification of a circulating inhibitor of sodium-potassium--dependent adenosine triphosphatase remains elusive. Dietary intervention trials of salt restriction in patients with hypertension are generally disappointing. Active research is elucidating the role of sodium intake and hypertension at all levels. The data to date, however, still do not allow sweeping conclusions or generalizations.     

ARTERIAL BARORECEPTOR REFLEX AND CALCIUM ANTAGONISTS

Summary— The tachycardia elicited by decreases in aortic pressure produced by various calcium antagonists, regardless of their chemical structures, is not always simply related to the reduction in pressure. Several experimental and clinical experiments have clearly demonstrated that some of these compounds interfer with the baroreceptor reflex control of heart rate. The voltage-dependent calcium channel blockade induced by these antagonists is probably not involved in the baroreceptor mechanotransduction, but central modulation of the baroreceptor reflex is probably an important site for action of these drugs at therapeutic levels. During chronic treatment of hypertension with calcium antagonists, a resetting of the reflex occurred with parallel shift of the set-point and of the baroreceptor reflex-response curve towards lower pressures, thus explaining the lack of change in heart rate despite a permanent reduction in blood pressure under these conditions. However, these effects of calcium antagonists on the baroreceptor reflex do not provide evidence that such interactions could play a role in their antihypertensive action during chronic therapy.     

A multicenter, community-based study of doxazosin in the treatment of concomitant hypertension and symptomatic benign prostatic hyperplasia: the Hypertension and BPH Intervention Trial (HABIT)

As men age, the incidence of both benign prostatic hyperplasia (BPH) and hypertension increases. Concomitant occurrence of these conditions also increases with age, and the 2 are frequently encountered together in primary care practice. In addition, many patients with hypertension require >1 antihypertensive agent to adequately control blood pressure. In a multicenter, community-based, 8-week, uncontrolled, open-label study, we evaluated doxazosin, a selective alpha1-adrenergic-receptor antagonist, in 491 patients with concomitant symptomatic BPH (American Urological Association [AUA] symptom score > or =12) and hypertension, some previously untreated and some with inadequately controlled hypertension (systolic blood pressure 120-179 mm Hg or diastolic blood pressure [DBP] 80-109 mm Hg) despite taking 1 or 2 antihypertensive agents. Patients were allocated to 1 of 4 groups at baseline according to their diastolic blood pressure (control was considered DBP <90 mm Hg) and whether they had received antihypertensive medication before the study. Thus the 4 groups were treated/well-controlled, treated/poorly controlled, untreated/hypertensive, and untreated/normotensive. In all patient groups, doxazosin therapy significantly improved AUA total symptom and bothersomeness scores and BPH-specific indices of health status and interference with activities (P<0.001). Significant improvements in BPH symptoms were observed with doxazosin, regardless of whether initial symptoms were moderate or severe (P<0.001). Clinically important blood pressure lowering occurred only in the patient groups in which blood pressure had been elevated at baseline. Patients whose blood pressure was poorly controlled at baseline, either without or with treatment (predominantly with angiotensin-converting enzyme inhibitors or calcium channel blockers), achieved adequate blood pressure control (reduction to <140/90 mm Hg) with the addition of doxazosin. Similar improvements in blood pressure and BPH symptoms were seen in both older (> or =65 years) and younger (45 to 64 years) patients, and doxazosin was well tolerated by both groups. The most frequent treatment-related adverse event was dizziness (13.0% of patients); however, patients classified the dizziness as mild in approximately 75% of reports, and severe dizziness was reported by only 2 patients (0.4%). Doxazosin is an effective antihypertensive agent when used in combination with agents from other antihypertensive classes in patients with poorly controlled hypertension and BPH, and is also successful as monotherapy for controlling both BPH and hypertension in patients with mild to moderate hypertension.     

Role of manidipine in the management of patients with hypertension

Manidipine is a third-generation dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. In clinical studies, manidipine has been shown to significantly lower office and 24-h blood pressure compared with placebo in patients with essential hypertension. The resulting reduction in blood pressure is maintained over 24 h, with preservation of the circadian blood pressure pattern; its blood pressure-lowering capacity appears to be similar to that of other calcium antagonists. In elderly patients with mild-to-moderate essential hypertension, manidipine is able to significantly decrease blood pressure compared with placebo for up to 3 years of treatment. The drug also significantly lowers blood pressure in patients with hypertension and concomitant Type 2 diabetes mellitus or renal impairment, and is devoid of adverse metabolic effects. It is well-tolerated with few untoward adverse effects related to vasodilation. In particular, manidipine appears to have less potential for pedal edema than other calcium channel blockers.     

Role of manidipine in the management of patients with hypertension

Manidipine is a third-generation dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. In clinical studies, manidipine has been shown to significantly lower office and 24-h blood pressure compared with placebo in patients with essential hypertension. The resulting reduction in blood pressure is maintained over 24 h, with preservation of the circadian blood pressure pattern; its blood pressure-lowering capacity appears to be similar to that of other calcium antagonists. In elderly patients with mild-to-moderate essential hypertension, manidipine is able to significantly decrease blood pressure compared with placebo for up to 3 years of treatment. The drug also significantly lowers blood pressure in patients with hypertension and concomitant Type 2 diabetes mellitus or renal impairment, and is devoid of adverse metabolic effects. It is well-tolerated with few untoward adverse effects related to vasodilation. In particular, manidipine appears to have less potential for pedal edema than other calcium channel blockers.     

Labile hypertension in elderly: clinical features, autonomic regulation of circulation, approaches to treatment

Blood pressure in some elderly hypertensive patients is characterized by marked lability. This affects quality of life and may deteriorate prognosis. Conventional anti-hypertensive medication does not lead to stabilization of blood pressure. We call this form of hypertension "labile hypertension of the elderly" (LHE). The aim of the study was investigation of autonomic regulation of blood pressure and of clonazepam effectiveness in patients with LHE. Fifty-six patients with LHE (mean age 67.0 +/- 6.3 years) entered the study (87.5% women). Control group consisted of 38 patients with stable hypertension and 27 normotensives matched by sex and age. The patients and the controls underwent clinical and psychological examinations, regular measurement of blood pressure during one month before and after the treatment, cardiovascular tests and spectral analysis of the heart rate variability. It was found that LHE patients have higher level of anxiety and depression, low standard deviation of RR interval, low normalized LF and HF components and increased normalized VLF component. The cardiovascular tests showed signs of diminished parasympathetic regulation. Clonazepam treatment in a dose 1-2 mg/day brought about a significant stabilization of blood pressure in 82.0% of patients with LHE. Thus, LHE is an original form of hypertension in patients over 60 years old characterized by frequent, short-term, small symptomatic, spontaneous fluctuations of blood pressure with development of both hypertensive and hypotensive reactions. Pathogenesis of LHE is linked with disorders of heart rate autonomic regulation, marked anxiety and depression. Clonazepam stabilizes blood pressure in most LHE cases.     

The role of the autonomic nervous system in hypertension: a bond graph model study

A bond graph model of the cardiovascular system with embedded autonomic nervous regulation was developed for a better understanding of the role of the autonomic nervous system (ANS) in hypertension. The model is described by a pump model of the heart and a detailed representation of the head and neck, pulmonary, coronary, abdomen and extremity circulation. It responds to sympathetic and parasympathetic activities by modifying systemic peripheral vascular resistance, heart rate, ventricular end-systolic elastance and venous unstressed volumes. The impairment of ANS is represented by an elevation of the baroreflex set point. The simulation results show that, compared with normotensive, in hypertension the systolic and diastolic blood pressure (SBP/DBP) rose from 112/77 mmHg to 144/94 mmHg and the left ventricular wall thickness (LVWT) increased from 10 mm to 12.74 mm. In the case that ANS regulation was absent, both the SBP and DBP further increased by 8 mmHg and the LVWT increased to 13.22 mm. The results also demonstrate that when ANS regulation is not severely damaged, e.g. the baroreflex set point is 97 mmHg, it still has an effect in preventing the rapid rise of blood pressure in hypertension; however, with the worsening of ANS regulation, its protective role weakens. The results agree with human physiological and pathological features in hemodynamic parameters and carotid baroreflex function curves, and indicate the role of ANS in blood pressure regulation and heart protection. In conclusion, the present model may provide a valid approach to study the pathophysiological conditions of the cardiovascular system and the mechanism of ANS regulation.     

Insulin-dependent diabetes mellitus and hypertension

Contrasting results have been reported regarding the prevalence of hypertension in insulin-dependent diabetes mellitus (IDDM), showing a slightly higher or normal percentage of IDDM patients with elevated blood pressure levels than in the general population. Most of the cross-sectional and prospective studies on the prevalence of hypertension in IDDM show an association between microalbuminuria and elevated blood pressure levels. However, it is not clear whether hypertension is simply secondary to kidney damage or whether hypertension occurs with or even before the development of impaired kidney function. Patients with IDDM have a higher exchangeable body Na+ pool. Na+ retention in IDDM is accounted for by several metabolic and hormonal abnormalities such as hyperglycemia, hyperketonemia, hyperinsulinemia, altered secretion, and resistance to atrial natriuretic peptide. High blood pressure appears to be dependent, at least at some phase, on expansion of extracellular fluid volume as a consequence of defects in the renal secretion of Na+ and water. On the other hand, a tendency toward Na+ retention characterizes all patients with IDDM, whereas hypertension develops only in a subgroup of diabetic patients. One possible explanation for these findings is that a genetic predisposition plays a role in creating susceptibility to hypertension and perhaps to diabetic nephropathy independent of diabetes, even if Na+ retention can further deteriorate this susceptibility to hypertension. With regard to this issue, it has recently been suggested that the risk of kidney disease in patients with IDDM is associated with a genetic predisposition to hypertension. Furthermore, diabetic nephropathy occurs in familial clusters, because diabetic siblings of nephropathic diabetic patients show a higher frequency of diabetic nephropathy than the diabetic siblings of nonnephropathic diabetic patients. One of the possible genetic markers that could be useful to identify the diabetic patients with susceptibility to hypertension and diabetic nephropathy is the Na+(-)Li+ countertransport activity in erythrocytes.     

Valsartan-amlodipine-hydrochlorothiazide: the definitive fixed combination?

A significant proportion of patients with hypertension will need three or more antihypertensive agents to achieve blood pressure goals, particularly those at higher risk. On the other hand, fixed combinations provide an extra beneficial effect, as they improve medication adherence and, secondarily, the attainment of blood pressure goals during follow-up. Triple therapy is recommended in the treatment of hypertension in those patients not adequately controlled with two antihypertensive drugs. In this context, guidelines recommend the combination of a renin-angiotensin system inhibitor, a calcium channel blocker and a diuretic. The triple fixed combination of valsartan-amlodipine-hydrochlorothiazide has been shown to be an effective and safe therapy for treating hypertension and seems a logical approach for those patients uncontrolled with two antihypertensive agents as well as in those patients already treated with three drugs to improve treatment compliance. In this article, available evidence about the efficacy and tolerability of the triple fixed combined therapy valsartan-amlodipine-hydrochlorothiazide for the treatment of hypertension is updated.     

Hypertension and atherosclerosis

Sufficient evidence exists to implicate hypertension as a potent independent risk factor for the development of atherosclerosis. Whereas certain biochemical pathways may play some role in the genesis of atherosclerosis in patients with hypertension, the blood pressure level alone may accelerate the atherosclerotic process. This article discusses the link between hypertension, atherosclerosis, and antihypertensive therapy.     

Platelet cytosolic free calcium concentration, total plasma calcium concentration and blood pressure in human twins: a genetic analysis.

1. We used path analysis and maximum-likelihood model fitting to evaluate the relative contributions of genetic and environmental factors to the relationships observed between level of blood pressure and both total plasma calcium concentration and platelet cytosolic free calcium concentration in 109 twin pairs. 2. Total plasma calcium concentration was positively associated with systolic (r = 0.26, P less than 0.001) but not diastolic blood pressure, a relationship which remained significant after adjustment for albumin, age and body mass index. A relationship between platelet cytosolic free calcium concentration and both systolic and diastolic blood pressure (r = 0.17 and r = 0.13, respectively, P less than or equal to 0.05) was no longer significant after adjustment for age and body mass index. 3. Additive genetic influences, unique environmental effects and age contributed to 60%, 30% and 10% of the variance in systolic blood pressure, respectively. Additive genetic effects explained 78% of the variance in plasma total calcium concentration and at least 48% of the variance in platelet cytosolic free calcium concentration in females and 37% in males. 4. Bivariate factor models provided evidence of genetic, but not environmental, co-variation of total plasma calcium concentration and systolic blood pressure, suggesting that a common genetic factor (or factors) contributes to their univariate relationship. In contrast, there was evidence of environmental, but not genetic, covariation of platelet cytosolic free calcium concentration and systolic blood pressure, suggesting that some of the individual experiences specific to each twin may be causing these two traits to vary together. 5. The possible confounding effects of adiposity and environmental factors should be considered in future studies investigating the role of intracellular calcium levels in the pathogenesis of hypertension.     

Increased levels of CD40-CD40 ligand system in patients with essential hypertension

BACKGROUND: Although it has been hypothesized that hypertension is in part an inflammatory disorder, clinical data linking inflammation with incident hypertension are scarce. There is evidence that have shown that CD40-CD40L interaction plays a pathogenic role in inflammatory disorders. We assessed whether CD40 system expressions were altered in patients including 30 with hypertension grade 1, 80 with hypertension grade 2 and 40 with hypertension grade 3. METHODS: Twenty normal controls and 150 patients with essential hypertension were investigated. The expression of CD40 and CD40L on platelet was analyzed by indirect-immunofluorescence flow cytometry and soluble CD40L level was determined by a commercially available ELISA. C-reactive protein was also measured by ELISA. RESULTS: All patients with hypertension showed a significant increase of CD40 (67.1+/-9.6 Mean Fluorescence Intensity, MFI) and CD40L (15.3+/-5.0 MFI) coexpression on platelets as well as sCD40L levels (12.8+/-3.9 ng/ml ) compared with controls (p<0.0001). We found that CRP levels related to CD40-CD40L system. We also observed a slight correlation between sCD40L level and blood pressure. During 3 months follow-up, patients with enhanced levels of sCD40L (>15 ng/ml) indicated a tough control of blood pressure. CONCLUSION: Patients with essential hypertension show increased coexpression of CD40 system, which suggests that hypertension is in part an inflammatory disorder.     

Etiology and prevalence of hypertension in diabetic patients

Data from several epidemiologic studies have suggested that the prevalence of hypertension in patients with diabetes mellitus is approximately 1.5-2.0 times greater than in an appropriately matched nondiabetic population. In patients with insulin-dependent diabetes mellitus (IDDM), hypertension is generally not present at the time of diagnosis. As renal insufficiency develops, blood pressure rises and may exacerbate the progression to end-stage renal failure. In non-insulin-dependent diabetes mellitus (NIDDM), many patients are hypertensive at the time of diagnosis. The incidence of hypertension in NIDDM is related to the degree of obesity, advanced age, and extensive atherosclerosis that is typically present, and it probably includes many patients with essential hypertension. Several other pathophysiologic mechanisms also contribute to the genesis and maintenance of hypertension in the patient with diabetes. Hyperglycemia and increases in total-body exchangeable sodium may lead to extracellular fluid accumulation and expansion of the plasma volume. In some patients, alterations in the function of the renin-angiotensin-aldosterone system and vascular sensitivity to vasoactive hormones may also play a role. It has recently been suggested that hyperinsulinemia and insulin resistance may also contribute to the maintenance of an elevated blood pressure because insulin is known to promote sodium retention and enhance sympathetic nervous system activity. The evidence for these hypotheses and their respective contributions to the etiology of hypertension in IDDM and NIDDM are discussed.     

Valsartan–amlodipine–hydrochlorothiazide: the definitive fixed combination?

A significant proportion of patients with hypertension will need three or more antihypertensive agents to achieve blood pressure goals, particularly those at higher risk. On the other hand, fixed combinations provide an extra beneficial effect, as they improve medication adherence and, secondarily, the attainment of blood pressure goals during follow-up. Triple therapy is recommended in the treatment of hypertension in those patients not adequately controlled with two antihypertensive drugs. In this context, guidelines recommend the combination of a renin–angiotensin system inhibitor, a calcium channel blocker and a diuretic. The triple fixed combination of valsartan–amlodipine–hydrochlorothiazide has been shown to be an effective and safe therapy for treating hypertension and seems a logical approach for those patients uncontrolled with two antihypertensive agents as well as in those patients already treated with three drugs to improve treatment compliance. In this article, available evidence about the efficacy and tolerability of the triple fixed combined therapy valsartan–amlodipine–hydrochlorothiazide for the treatment of hypertension is updated.     

Therapeutic implications of sodium abnormalities in hypertension

Abnormalities in cellular sodium transport have been demonstrated in leukocytes and erythrocytes of some patients with essential hypertension. Some patients with essential hypertension retain more sodium on a high-salt diet, despite an accompanying increase in pressure. Some epidemiological studies suggest a relationship between dietary sodium intake and essential hypertension. The biological significance of these findings remains uncertain. There is too little evidence to support dietary sodium restriction as a primary preventive measure in essential hypertension. Restriction of dietary intake of sodium to 80 mmol/day results in a reduction in blood pressure in a minority of patients with essential hypertension.